The present invention relates to pharmaceutical compositions and methods of treating diseases therewith.
Fatty acids have been proposed as excipients in pharmaceutical compositions of unconjugated drug molecules. For example, U.S. Pat. No. 4,338,306 to Kitao et al. proposes pharmaceutical compositions for rectal administration of insulin. The pharmaceutical compositions include insulin and fatty acids having 8 to 14 carbon atoms and nontoxic salts thereof.
U.S. Pat. No. 5,658,878 to Bxc3xa4ckstrxc3x6m et al. proposes a therapeutic preparation for inhalation that includes insulin and a substance which enhances the absorption of insulin in the lower respiratory tract. The enhancer is preferably a sodium salt of a saturated fatty acid of carbon chain length 10 (i.e., sodium caprate), 12 (sodium laurate), or 14 (sodium myristate). Potassium and lysine salts of capric acid are also proposed. Bxc3xa4ckstrxc3x6m et al. note that if the carbon chain length is shorter than about 10, the surface activity of the surfactant may be too low, and if the chain length is longer than about 14, decreased solubility of the fatty acid in water limits its usefulness. As an alternative to the proposed fatty acid enhancers, Bxc3xa4ckstrxc3x6m et al. propose the use of the following bile saltsxe2x80x94sodium ursodeoxycholate, sodium taurocholate, sodium glycocholate, and sodium taurodihydrofusidate.
U.S. Pat. No. 6,200,602 to Watts et al. proposes drug delivery compositions for colonic delivery of insulin. The drug delivery compositions include insulin, an absorption promoter which (a) includes a mixture of fatty acids having 6 to 16 carbon atoms or a salt thereof and a dispersing agent, or (b) comprises a mixture of mono/diglycerides of medium chain fatty acids and a dispersing agent, and a coating to prevent the release of the insulin and absorption promoter until the tablet, capsule or pellet reaches the proximal colon.
Bile salts have been proposed as excipients in pharmaceutical compositions of unconjugated drug molecules. For example, U.S. Pat. No. 4,579,730 to Kidron et al. proposes pharmaceutical compositions for the oral administration of insulin. The pharmaceutical compositions include insulin, a bile acid or alkali metal salt thereof, the bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3xcex2-hydroxy-12-ketocholic acid, 12xcex1-3xcex2-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor. The composition is provided with an enterocoating to assure passage through the stomach and release in the intestine.
U.S. Pat. No. 5,283,236 to Chiou proposes compositions for systemic delivery of insulin through the eyes where the drug passes into the nasolacrimal duct and becomes absorbed into circulation. The composition includes insulin and an enhancing agent. The enhancing agents proposed include, either alone or in combination, surfactants such as polyoxyethylene ethers of fatty acids, and bile salts and acids such as cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium cholate, sodium glycocholate, glycocholate, sodium deoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid, and ursodeoxycholic acid. The enhancer is present in a concentration ranging from 0.1% to 5% (w/v).
U.S. Pat. No. 5,853,748 to New proposes enteric-coated compositions for oral administration of insulin. The composition includes insulin, a bile salt or bile acid, and carbonate or bicarbonate ions, which are used to adjust the pH of the gut to a pH of from 7.5 to 9.
In at least one instance, a mixture of a low detergent bile salt, such as ursodeoxycholate, and a C12 to C24 fatty acid, such as linoleic or oleic acid, has been proposed as excipients in a pharmaceutical composition of orally acitve pharmaceutically active agents that need to be protected from the acidic and enzymatic environment of the stomach and for which the gastrointestinal mucosa should be protected from adverse effects of the drug. The proposed pharmaceutical composition is proposed to be particularly suitable for the non-steroidal anti-inflammatory drug indomethacin.
It is desirable to provide pharmaceutical compositions for administration of drug-oligomer conjugates.
Pharmaceutical compositions according to embodiments of the present invention use a mixture of bile salts and fatty acids in a particular ratio that appears to provide synergistic effects in the administration of drug-oligomer conjugates that may not be achieved with bile salts or fatty acids alone. For example, in some embodiments of the present invention, using mixtures of bile salts and fatty acids in a particular ratio alters the precipitation characteristics of the bile salt so that the bile salt more readily re-solubilizes if it happens to precipitate out of the pharmaceutical composition (e.g., upon encountering an acidic environment in the gut). As another example, in some embodiments of the present invention, using mixtures of bile salts and fatty acids in a particular ratio lowers the precipitation point of the bile salt in the pharmaceutical composition, providing additional buffering capacity for the pharmaceutical composition.
According to embodiments of the present invention, a pharmaceutical composition includes a drug-oligomer conjugate that includes a drug covalently coupled to an oligomeric moiety, a fatty acid component that includes a fatty acid, and a bile salt component that includes a bile salt. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1. The fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition. The bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition.
According to other embodiments of the present invention, a pharmaceutical composition includes a drug-oligomer conjugate that includes a drug covalently coupled to an oligomeric moiety, a bile salt component that includes a bile salt, and a fatty acid component that includes a fatty acid. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1. The fatty acid component is present in a first amount such that, at the precipitation point of the bile salt, the bile salt precipitates as first bile salt particles that, upon a return to a pH above the precipitation point of the bile salt, re-solubilize more quickly than second bile salt particles that would have precipitated if the fatty acid component were present in a second amount less than the first amount.
According to still other embodiments of the present invention, a pharmaceutical composition includes a drug-oligomer conjugate that includes a drug covalently coupled to an oligomeric moiety, between 0.1 and 15% (w/v) of a fatty acid component, and between 0.1 and 15% (w/v) of a bile salt component. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1.
According to other embodiments of the present invention, methods of treating a disease state in a subject in need of such treatment include administering to the subject a pharmaceutical composition according to embodiments of the present invention.
According to still other embodiments of the present invention, a method of providing a pharmaceutical composition includes selecting an amount of a bile salt to include in the composition based on the ability of the bile salt to increase the solubility of a fatty acid component when the composition has a pH of 8.5 or less.
According to yet other embodiments of the present invention, a method of providing a pharmaceutical composition includes selecting an amount of a fatty acid to include in the composition based on the ability of the fatty acid to lower the precipitation point of a bile salt component in the composition to a pH of 5.5 or less.
According to other embodiments of the present invention, a method of providing a pharmaceutical composition includes selecting an amount of a fatty acid to include in the composition based on the ability of the fatty acid to alter the precipitation characteristics of a bile salt component in the composition.